Department of Internal Medicine, VCU Medical Center, Richmond, VA, 23298, USA; Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA, 23219, USA.
Department of Internal Medicine, VCU Medical Center, Richmond, VA, 23298, USA.
Biomaterials. 2020 Nov;260:120333. doi: 10.1016/j.biomaterials.2020.120333. Epub 2020 Aug 15.
Reduction of lipoprotein uptake by macrophages and stimulation of cholesterol efflux are two essential steps required for atherosclerotic plaque regression. We used the optimized mannose-functionalized dendrimeric nanoparticle (mDNP)-based platform for macrophage-specific delivery of therapeutics to simultaneously deliver SR-A siRNA (to reduce LDL uptake) and LXR ligand (LXR-L, to stimulate cholesterol efflux) - a novel "Two-pronged" approach to facilitate plaque regression. mDNP-mediated delivery of SR-A siRNA led to a significant reduction in SR-A expression with a corresponding decrease in uptake of oxLDL. Delivery of LXR-L increased expression of ABCA1/G1 and cholesterol efflux. Combined delivery of siRNA and LXR-L led to a significantly greater decrease in macrophage cholesterol content compared to either treatment alone. Administration of this in vitro optimized formulation of mDNP complexed with SR-A-siRNA and LXR-L (Two-pronged complex) to atherosclerotic LDLR-/- mice fed western diet (TD88137) led to significant regression of atherosclerotic plaques with a corresponding decrease in aortic cholesterol content.
减少巨噬细胞对脂蛋白的摄取和刺激胆固醇外排是动脉粥样硬化斑块消退所必需的两个关键步骤。我们使用优化的甘露糖功能化树枝状纳米颗粒（mDNP）平台，实现了治疗剂对巨噬细胞的特异性递送，同时递送 SR-A siRNA（降低 LDL 摄取）和 LXR 配体（LXR-L，刺激胆固醇外排）——这是一种促进斑块消退的新“双管齐下”方法。mDNP 介导的 SR-A siRNA 递送导致 SR-A 表达显著减少，相应地降低了 oxLDL 的摄取。LXR-L 的递送增加了 ABCA1/G1 的表达和胆固醇外排。与单独治疗相比，siRNA 和 LXR-L 的联合递送导致巨噬细胞胆固醇含量显著降低。将这种体外优化的 mDNP 复合物与 SR-A-siRNA 和 LXR-L（双管齐下的复合物）施用于喂食西方饮食（TD88137）的动脉粥样硬化 LDLR-/- 小鼠，导致动脉粥样硬化斑块显著消退，主动脉胆固醇含量相应降低。
